ATP-Sensitive Potassium Channels in Health and Disease

  • Peter Proks
  • Frances M. Ashcroft


Since their discovery over 20 years ago, it has been recognized that adenosine triphosphate-sensitive potassium (KATP) channels play a critical role in insulin secretion. When these channels are open, insulin secretion is inhibited, and when they are shut, secretion is initiated. Consequently drugs, mutations, or changes in beta-cell metabolism that open KATP channels decrease insulin secretion and may cause diabetes, whereas those manipulations that close KATP channels have the opposite effect, increasing insulin secretion and hypoglycemia. This chapter reviews our current knowledge of the pancreatic beta-cell KATP channel, and discusses new data on its structure, structure-function relationships, and role in disease.


Insulin Secretion Beta Cell Neonatal Diabetes Congenital Hyperinsulinism Transient Neonatal Diabetes 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Ashcroft FM, Harrison DE, Ashcroft SJH (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta cells. Nature 312:446–448PubMedCrossRefGoogle Scholar
  2. 2.
    Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54:87–143PubMedCrossRefGoogle Scholar
  3. 3.
    Seino S, Miki T (2003) Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol 81:133–176PubMedCrossRefGoogle Scholar
  4. 4.
    Inagaki N, Gonoi T, Seino S (1997) Subunit stoichiometry of the pancreatic beta-cell ATP-sensitive K+ channel. FEBS Lett 409:232–236PubMedCrossRefGoogle Scholar
  5. 5.
    Zerangue N, Schwappach B, Jan YN, Jan LY (1999) A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron 22:537–548PubMedCrossRefGoogle Scholar
  6. 6.
    Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M, Seino Y, Mizuta M, Seino S (1995) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J Biol Chem 270:5691–5694PubMedCrossRefGoogle Scholar
  7. 7.
    Sakura H, Ämmalä C, Smith PA, Gribble FM, Ashcroft FM (1995) Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta cells, brain, heart and skeletal muscle. FEBS Lett 377:338–344PubMedCrossRefGoogle Scholar
  8. 8.
    Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft FM (1997) Truncation of Kir6.2 produces ATP-sensitive K channels in the absence of the sulfonylurea receptor. Nature 387:179–181PubMedCrossRefGoogle Scholar
  9. 9.
    Markworth E, Schwanstecher C, Schwanstecher M (2000) ATP4− mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites. Diabetes 49:1413–1418PubMedCrossRefGoogle Scholar
  10. 10.
    Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP IV, Boyd AE III, Gonzalez Herrerasosa H, Nguy K, Bryan J, Nelson DA (1995) Cloning of the beta-cell high-affinity sulphonylurea receptor: a regulator of insulin secretion. Science 268: 423–425PubMedCrossRefGoogle Scholar
  11. 11.
    Aguilar-Bryan L, Bryan J (1999) Molecular biology of adenosine triphosphate sensitive potassium channels. Endocr Rev 20:101–135PubMedCrossRefGoogle Scholar
  12. 12.
    Masia R, Enkvetchakul D, Nichols CG (2005) Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. J Mol Cell Cardiol 39:491–501PubMedCrossRefGoogle Scholar
  13. 13.
    Zingman LV, Alekseev AE, Bienengraeber M, Hodgson D, Karger AB, Dzeja PP, Terzic A (2001) Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance. Neuron 31:233–245PubMedCrossRefGoogle Scholar
  14. 14.
    Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B, Collins RF, Sansom MSP, Ford RC, Ashcroft FM (2005) 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. EMBO J 24:4166–4175PubMedCrossRefGoogle Scholar
  15. 15.
    Nichols CG, Shyng SL, Nestorowicz A (1996) Adenosine diphosphate as an intracellular regulator of insulin secretion. Science: 272:1785–1787PubMedCrossRefGoogle Scholar
  16. 16.
    Gribble FM, Tucker SJ, Ashcroft FM (1997) The essential role of the Walker A motifs of SUR1 in KATP channel activation by Mg-ADP and diazoxide. EMBO J 16: 1145–1152PubMedCrossRefGoogle Scholar
  17. 17.
    Gribble FM, Tucker SJ, Haug T, Ashcroft FM (1998) MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit. Proc Natl Acad Sci USA 95:7185–7190PubMedCrossRefGoogle Scholar
  18. 18.
    Reimann F, Gribble FM, Ashcroft FM (2000) Differential response of KATP channels containing SUR2A or SUR2B subunits to nucleotides and pinacidil. Mol Pharmacol 58:1318–1325PubMedGoogle Scholar
  19. 19.
    Gribble FM, Reimann F (2003) Sulphonylurea action revisited: the post-cloning era. Diabetologia 46:875–891PubMedCrossRefGoogle Scholar
  20. 20.
    Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino, S (1996) A family of sulfonylurea receptors determines the properties of ATP-sensitive K+ channels. Neuron 16:1011–1017PubMedCrossRefGoogle Scholar
  21. 21.
    Isomoto S, Kondo C, Yamada M, Matsumoto S, Higashiguchi O, Horio Y, Matsuzawa Y, Kurachi Y (1996) A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J Biol Chem 271:24321–24324PubMedCrossRefGoogle Scholar
  22. 22.
    Ashcroft, FM (2005) ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 115:2047–2058PubMedCrossRefGoogle Scholar
  23. 23.
    Tarasov AI, Girard CAJ, Ashcroft FM (2006) ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic beta cells. Diabetes 55:2446–2454PubMedCrossRefGoogle Scholar
  24. 24.
    Niki I, Ashcroft FM, Ashcroft SJH (1989) The dependence on intracellular concentration of ATP-sensitive K-channels and of Na-K-ATPase in intact HIT-T15 beta cells. FEBS Lett 257:361–364PubMedCrossRefGoogle Scholar
  25. 25.
    Kakei M, Kelly RP, Ashcroft SJH, Ashcroft FM (1986) The ATP-sensitivity of K+ channels in rat pancreatic beta cells is modulated by ADP. FEBS Lett 208:63–66PubMedCrossRefGoogle Scholar
  26. 26.
    Dunne MJ, Petersen OH (1986) Intracellular ADP activates ATP-sensitive K+ channels in an insulin-secreting cell line. FEBS Lett 208:59–62PubMedCrossRefGoogle Scholar
  27. 27.
    Fan Z, Makielski JC (1997) Anionic phospholipids activate ATP-sensitive potassium channels J Biol Chem 272:5388–5395PubMedCrossRefGoogle Scholar
  28. 28.
    Baukrowitz T, Fakler B (2000) KATP channels: Linker between phospholipid metabolism and excitability. Biochem Pharmacol 60:735–740PubMedCrossRefGoogle Scholar
  29. 29.
    Larsson O, Deeney JT, Bränström R, Berggren PO, Corkey BE (1996) Activation of the ATP-sensitive K+ channels by long chain acyl-CoA. J Biol Chem 271:10623–10626PubMedCrossRefGoogle Scholar
  30. 30.
    Gribble FM, Proks P, Corkey BE, Ashcroft (1998) Mechanism of cloned KATP channel activation by oleyol-CoA. J Biol Chem 273:26383–26387PubMedCrossRefGoogle Scholar
  31. 31.
    Eliasson L, Renstrom E, Ammala C, Berggren PO, Bertorello AM, Bokvist K, Chibalin A, Deeney JT, Flatt PR, Gabel J, Gromada J, Larsson O, Lindstrom P, Rhodes CJ, Rorsman P (1996) PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta cells. Science 271:813–815PubMedCrossRefGoogle Scholar
  32. 32.
    GarciaBarrado MJ, Jonas JC, Gilon P, Henquin JC (1996) Sulphonylureas do not increase insulin secretion by a mechanism other than a rise in cytoplasmic Ca2+ in pancreatic B-cells. Eur J Pharmacol 298:279–286CrossRefGoogle Scholar
  33. 33.
    Gribble FM, Tucker SJ, Seino S, Ashcroft FM (1998) Tissue specificity of sulphonylureas: studies on cloned cardiac and beta cell KATP channels. Diabetes 47:1412–1418PubMedCrossRefGoogle Scholar
  34. 34.
    United Kingdom Prospective Diabetes Study (UKPDS) 13 (1995) Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 310:83–88Google Scholar
  35. 35.
    Gribble FM, Tucker SJ, Ashcroft FM (1997) The interaction of nucleotides with the tolbutamide block of KATP currents: a reinterpretation. J Physiol 504:35–45PubMedCrossRefGoogle Scholar
  36. 36.
    Dabrowski M, Wahl P, Holmes WE, Ashcroft FM (2001) Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channel. Diabetologia 44:747–756PubMedCrossRefGoogle Scholar
  37. 37.
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining JG, Slingerland AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, Edghill EL, Frayling TM, Temple IK, Deborah Mackay D, Shield JPH, Sumnik Z, van Rhijn A, Wales JKH, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849PubMedCrossRefGoogle Scholar
  38. 38.
    Hattersley AT, Ashcroft FM (2005) Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513PubMedCrossRefGoogle Scholar
  39. 39.
    Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJG, Shield JPH, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 14:925–934PubMedCrossRefGoogle Scholar
  40. 40.
    Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y, Hosokawa M, Yamada Y, Inagaki N, Nakahata T (2005) The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab 90:3174–3178PubMedCrossRefGoogle Scholar
  41. 41.
    Gloyn AL, Siddiqui J, Ellard S (2006) Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 27:220–231PubMedCrossRefGoogle Scholar
  42. 42.
    Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S (2006) A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 15:1793–1800PubMedCrossRefGoogle Scholar
  43. 43.
    Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355:456–466PubMedCrossRefGoogle Scholar
  44. 44.
    Proks P, Antcliff JF, Lippiat J, Gloyn A, Hattersley AT, Ashcroft FM (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 101:17539–17544PubMedCrossRefGoogle Scholar
  45. 45.
    Proks P, Girard C, Haider S, Gloyn AL, Hattersley AT, Sansom MSP, Ashcroft FM (2005) A novel gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. EMBO Rep 6:470–475PubMedCrossRefGoogle Scholar
  46. 46.
    Proks P, Girard C, Ashcroft FM (2005) Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet 14:2717–2726PubMedCrossRefGoogle Scholar
  47. 47.
    Proks P, Girard C, Bævre H, Njolstad PR, Ashcroft FM (2006) Functional effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulphonylurea therapy. Diabetes 55:1731–1737PubMedCrossRefGoogle Scholar
  48. 48.
    Shimomura K, Girard C, Proks P, Nazim J, Lippiat JD, Cerutti F, Lorini R, Ellard S, Hattersley AT, Barbetti F, Ashcroft FM (2006) Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects. Diabetes 55:1705–1712PubMedCrossRefGoogle Scholar
  49. 49.
    Tammaro P, Girard C, Molnes J, Njølstad PR, Ashcroft FM (2005) Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions. EMBO J 24:2318–2330PubMedCrossRefGoogle Scholar
  50. 50.
    Tammaro P, Proks P, Ashcroft FM (2006) Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac KATP channels. J Physiol 571:3–14PubMedCrossRefGoogle Scholar
  51. 51.
    Girard C, Shimomura K, Proks P, Absalom N, de Nanclares PG, Ashcroft FM (2006) Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch 453:323–332PubMedCrossRefGoogle Scholar
  52. 52.
    Tarasov A, Welters HJ, Senkel S, Ryffel GU, Hattersley AT, Morgan NG, Ashcroft FM (2006) A Kir6.2 mutation causing neonatal diabetes impairs electrical activity and insulin secretion from INS-1 beta cells. Diabetes 55:3075–3082PubMedCrossRefGoogle Scholar
  53. 53.
    Erecinska M, Bryla J, Michalik M, Meglasson MD, Nelson D (1992) Energy-metabolism in islets of Langerhans. Biochim Biophys Acta 1101:273–295PubMedCrossRefGoogle Scholar
  54. 54.
    Trapp S, Proks P, Tucker SJ, Ashcroft FM (1998) Molecular Analysis of KATP channel gating and implications for channel inhibition by ATP. J Gen Physiol 112:333–349PubMedCrossRefGoogle Scholar
  55. 55.
    Enkvetchakul D, Loussouarn G, Makhina E, Nichols CG (2001) ATP interaction with the open state of the KATP channel. Biophys J 80:719–728PubMedCrossRefGoogle Scholar
  56. 56.
    Kuo AL, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300:1922–1926PubMedCrossRefGoogle Scholar
  57. 57.
    Antcliff JF, Haider S, Proks P, Sansom MSP, Ashcroft FM (2005) Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit EMBO J 24:229–239Google Scholar
  58. 58.
    Haider S, Grottesi A, Hall BA, Ashcroft FM, Sansom MSP (2005) Conformational dynamics of the ligand-binding domain of inward rectifier K channels as revealed by molecular dynamics simulations: Toward an understanding of Kir channel gating. Biophys J 88:3310–3320PubMedCrossRefGoogle Scholar
  59. 59.
    Babenko AP, Bryan J (2003) SUR domains that associate with and gate KATP pores define a novel gatekeeper. J Biol Chem 278:41577–41580PubMedCrossRefGoogle Scholar
  60. 60.
    Karschin C, Ecke C, Ashcroft FM, Karschin A (1997) Overlapping distribution of KATP channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett 401:59–64PubMedCrossRefGoogle Scholar
  61. 61.
    Flagg TP, Nichols CG (2005) Sarcolemmal KATP channels: what do we really know? J Mol Cell Cardiol 39:61–70PubMedCrossRefGoogle Scholar
  62. 62.
    Koster JC, Knopp A, Flagg TP, Markova KP, Sha Q, Enkvetchakul D, Betsuyaku T, Yamada KA, Nichols CG (2001) Tolerance for ATP-insensitive K-ATP channels in transgenic mice. Circ Res 89:1022–1029PubMedCrossRefGoogle Scholar
  63. 63.
    Matsuoka T, Matsushita K, Katayama Y, Fujita A, Inageda K, Tanemoto M, Inanobe A, Yamashita S, Matsuzawa Y, Kurachi Y (2000) C-terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K+ channels. Circ Res 87:873–880PubMedGoogle Scholar
  64. 64.
    Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert J, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355: 467–477PubMedCrossRefGoogle Scholar
  65. 65.
    Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ (2004) Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 84:239–275PubMedCrossRefGoogle Scholar
  66. 66.
    Glaser B (2000) Hyperinsulinism of the newborn. Semin Perinatol 24:150–163PubMedCrossRefGoogle Scholar
  67. 67.
    Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, Torri S, Pollera M, Boggi U, Mosca F, Del Prato S, Marchetti P (2005) Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54:727–735PubMedCrossRefGoogle Scholar
  68. 68.
    Ashcroft FM, Rorsman P (2004) Molecular defects in insulin secretion in type-2 diabetes. Rev Endocr Metab Disord 5:135–142PubMedCrossRefGoogle Scholar
  69. 69.
    Wollheim CB, Maechler P (2002) Beta-cell mitochondria and insulin secretion-Messenger role of nucleotides and metabolites. Diabetes 51(Suppl 1):S37–S42PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Peter Proks
    • 1
  • Frances M. Ashcroft
    • 1
  1. 1.Oxford Centre for Gene Function, Department of PhysiologyUniversity of OxfordOxfordUK

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